Insulin dependent diabetes mellitus (IDDM) is caused by a paucity of insulin-producing cells in the islets of Langerhans. In virtually all circumstances the islet cells have no regenerative capacity after birth and once they are destroyed by inflammatory cells no recovery is possible. In this proposal we will study the mechanism by which the insulin-producing beta cells are regenerated with the eventual goal of identifying specific factors that are critically involved in their development. For these studies we will utilize a strain of transgenic mice that has demonstrated a dramatically high level of pancreatic duct cell proliferation and neogenesis of islet cells during adult life. The experimental studies proposed in this application will distinguish between two potential models accounting for the observed regeneration. We will determine what potentially inductive molecules are present in the regenerating pancreas. The identity of cells required for the proliferation/differentiation will be established by perturbing the system genetically and through the use of mechanisms that allow the depletion of specific cell categories in the regenerating pancreas. Lastly, we will utilize an in vitro system to integrate the data collected from the studies on the transgenic mice. Cultures of pancreatic duct epithelial cells will be derived from both transgenic and non-transgenic animals. These duct cells cultures will be studied histologically and also for their ability to differentiate in vitro and in vivo. Lastly, we will design specific strategies, based upon the information gained in the proposed studies to induce islet cell differentiation in vitro. The proposed studies will augment the potential of inducing islet cell growth and regrowth as a means of replenishing the insulin producing machinery lost in IDDM.